• Kufs' disease
• neuronal ceroidlipofuscinosis
• occipital seizures
• photoparoxysmal response
• progressive myoclonus epilepsy

• Humans
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/physiopathology
• Neuronal Ceroid-Lipofuscinoses/complications
• Young Adult
• Phenotype
• Membrane Proteins/genetics
• Male
• Female
• Mutation/genetics

• RF-2019-12370491 Ministero dell'Università e della Ricerca
• Fondazione Pierfranco e Luisa Mariani
• Italian Ministry of Health (RRC)
• Ministero dell'Università e della Ricerca
• Fondazione Pierfranco e Luisa Mariani
• Italian Ministry of Health (RRC)

• Electron microscopy
• Electrophysiology
• Genetics
• Genotype-phenotype correlation
• Lysosomal storage disorders
• Neuroimaging
• Neuronal ceroid lipofuscinoses

• Humans
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/physiopathology
• Neuronal Ceroid-Lipofuscinoses/diagnostic imaging
• Male
• Female
• Genetic Association Studies
• Child, Preschool
• Retrospective Studies
• Child
• Tripeptidyl-Peptidase 1/genetics
• India
• Mutation
• Infant
• Membrane Proteins/genetics
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics
• Adolescent
• Serine Proteases/genetics
• Aminopeptidases/genetics
• Membrane Transport Proteins

• electron microscopy
• fluorescence
• lipofuscin
• lysosomal storage
• mitochondrial subunit c protein
• neurodegeneration
• whole genome sequencing

• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/veterinary
• Neuronal Ceroid-Lipofuscinoses/pathology
• Animals
• Dogs
• Male
• Dog Diseases/genetics
• Dog Diseases/pathology
• RNA Splice Sites/genetics
• Membrane Proteins/genetics
• Mitochondrial Proton-Translocating ATPases/genetics
• Brain/pathology
• Brain/metabolism
• Mutation

• R01 EY031674 NEI NIH HHS
• S10 OD032246 NIH HHS
• EY031674 U.S. National Institutes of Health

• Batten disease
• CLN6
• Hamburg scale
• Natural history

• Humans
• Child, Preschool
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Membrane Proteins/genetics
• Mutation/genetics
• Seizures
• Disease Progression

• Humans
• Iran
• Tripeptidyl-Peptidase 1
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Mutation
• Membrane Glycoproteins/genetics
• Molecular Chaperones/genetics
• Membrane Proteins/genetics
• Membrane Proteins/metabolism
• Membrane Transport Proteins/genetics

Neuronal ceroid lipofuscinoses (NCLs) comprise 13 hereditary neurodegenerative pathologies of very low frequency that affect individuals of all ages around the world. All NCLs share a set of symptoms that are similar to other diseases. The exhaustive collection of data from diverse sources (clinical, genetic, neurology, ophthalmology, etc.) would allow being able in the future to define this group with greater precision for a more efficient diagnostic and therapeutic approach. Despite the large amount of information worldwide, a detailed study of the characteristics of the NCLs in South America and the Caribbean region (SA&C) has not yet been done. Here, we aim to present and analyse the multidisciplinary evidence from all the SA&C with qualitative weighting and biostatistical evaluation of the casuistry. Seventy-one publications from seven countries were reviewed, and data from 261 individuals (including 44 individuals from the Cordoba cohort) were collected. Each NCL disease, as well as phenotypical and genetic data were described and discussed in the whole group. The CLN2, CLN6, and CLN3 disorders are the most frequent in the region. Eighty-seven percent of the individuals were 10 years old or less at the onset of symptoms. Seizures were the most common symptom, both at onset (51%) and throughout the disease course, followed by language (16%), motor (15%), and visual impairments (11%). Although symptoms were similar in all NCLs, some chronological differences could be observed. Sixty DNA variants were described, ranging from single nucleotide variants to large chromosomal deletions. The diagnostic odyssey was probably substantially decreased after medical education activities promoted by the pharmaceutical industry and parent organizations in some SA&C countries. There is a statistical deviation in the data probably due to the approval of the enzyme replacement therapy for CLN2 disease, which has led to a greater interest among the medical community for the early description of this pathology. As a general conclusion, it became clear in this work that the combined bibliographical/retrospective evaluation approach allowed a general overview of the multidisciplinary components and the epidemiological tendencies of NCLs in the SA&C region.

• Consejo Nacional de Investigaciones Científicas y Técnicas
• Fondo para la Investigación Científica y Tecnológica
• Universidad Nacional de Córdoba
• Batten Disease Support and Research Association

Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis.

We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic.

Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

• Batten disease
• CLN6
• Genotype
• Lysosomal storage disorder
• Neuronal ceroid lipofuscinoses
• New variant
• Phenotype
• Rare disease

• neurodegeneration
• retinal diseases

• Animals
• Atrophy
• Gliosis
• Membrane Proteins
• Neuronal Ceroid-Lipofuscinoses/pathology
• Retinal Degeneration
• Sheep

• Canterbury Medical Research Foundation
• Cure Kids
• Batten Disease Support and Research Association

Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population.

To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations.

DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records.

Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens.

This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

• Batten disease
• CNL6
• Lysosomal storage disease
• Neuronal ceroid lipofuscinosis
• Variant late infantile NCL
• vLINCL

• Amplification-refractory mutation system
• CLN6 gene
• Homozygous missense mutation
• PCR-RFLP

• CLN6
• Yakut family
• neuronal ceroid lipofuscinoses
• next-generation sequencing

• PUS3
• Jordan
• exome sequencing
• neurodevelopmental disorder

• Neuronal ceroid lipofuscinoses (NCL)
• adeno-associated virus (AAV)
• ceroid lipofuscinosis, neuronal (CLN)
• clinical trials
• enzyme replacement therapy (ERT)
• gene therapy
• palmitoyl protein thioesterase-1 (PPT1)
• tripeptidyl peptidase-1 (TPP1)

• R01 NS061848 NINDS NIH HHS
• U01 NS047458 NINDS NIH HHS

• CNL6
• Neuronal ceroid lipofuscinoses (NCL)
• Regression

• CLN2
• CLN5
• CLN6
• CLN7
• Neuronal Ceroid Lipofuscinosis (NCL)
• Next-Generation Sequencing (NGS)
• late-infantile

• Batten disease
• Lysosomal Storage Disorders
• Neuronal Ceroid Lipofuscinosis

• Adolescent
• Adult
• Child
• Exome/genetics
• Female
• Fibroblasts/chemistry
• High-Throughput Nucleotide Sequencing
• Humans
• Male
• Membrane Proteins/genetics
• Mutation
• National Institutes of Health (U.S.)
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Neuronal Ceroid-Lipofuscinoses/genetics
• Pedigree
• United States
• Vision Disorders

Late infantile ceroid lipofuscinosis is a rare neurodegenerative disorder that appears between the ages of 2 and 4 years and is difficult to diagnose. In this report we present two sisters with this condition, and the clinical course consisted of delayed developmental skills initially and later regression of previously acquired skills. The cases were initially considered as childhood disintegrative disorder (CDD); however, when whole exome sequencing (WES) genetic testing was done, they proved to be variant late infantile ceroid lipofuscinosis. This is the first report from Jordan.

Clinical presentation included developmental delay and initially speech delay, followed by lose of sphincter control. Motor development was normal until 4 years of age, then they developed ataxia (fear of going downstairs) and weakness while walking. Atonic and myoclonic seizures become intractable, and this was followed by inability to stand or sit and loss of expressive language. In addition to complete blood count test, liver function test, kidney function test, serum electrolyte test, and blood sugar test, serum amino acid profile, B12 level test, thyroid function test, and a brain computed tomography scan were also normal. An electroencephalogram showed a generalized spike and wave pattern, and magnetic resonance imaging showed little to no abnormalities. After dealing with the cases as CDD, WES testing proved a final diagnosis of variant late infantile ceroid lipofuscinosis. Current treatment is anti-epileptic drugs and supportive care at home, and they are now in vegetative state.

This report highlights the importance of WES for the identification of genetic diseases, especially neurodegenerative disorders.

• Ceroid lipofuscinosis
• Childhood disintegrative disorder
• Lysosomal storage disorders
• Neurodegenerative disorders
• Variant late infantile
• Case report

CLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression.

A number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females.

Thus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies.

The online version of this article (10.1186/s13023-019-0994-8) contains supplementary material, which is available to authorized users.

• Lysosomal storage disorder
• Neurodegenerative disease
• Neuronal ceroid lipofuscinoses
• Pediatric disease
• Rare disease

• CLN6
• Late infantile neuronal ceroid lipofudcinosis
• Whole-exome sequencing

• Adolescent
• Asian People/genetics
• Brain/diagnostic imaging
• Brain/physiopathology
• DNA Mutational Analysis
• Diagnosis, Differential
• Electroencephalography
• Humans
• Japan
• Magnetic Resonance Imaging
• Male
• Membrane Proteins/genetics
• Mutation
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/physiopathology
• Sequence Homology, Amino Acid

• Algorithm
• DNA variants
• Enzymes
• Morphology
• Neuronal ceroid lipofuscinoses

In the present study we aimed: 1) To establish the prevalence and clinical impact of DFNB49 mutations in deaf Roma from 2 Central European countries (Slovakia and Hungary), and 2) to analyze a possible common origin of the c.1331+2T>C mutation among Roma and Pakistani mutation carriers identified in the present and previous studies.

We sequenced 6 exons of the MARVELD2 gene in a group of 143 unrelated hearing impaired Slovak Roma patients. Simultaneously, we used RFLP to detect the c.1331+2T>C mutation in 85 Hungarian deaf Roma patients, control groups of 702 normal hearing Romanies from both countries and 375 hearing impaired Slovak Caucasians. We analyzed the haplotype using 21 SNPs spanning a 5.34Mb around the mutation c.1331+2T>C.

One pathogenic mutation (c.1331+2T>C) was identified in 12 homozygous hearing impaired Roma patients. Allele frequency of this mutation was higher in Hungarian (10%) than in Slovak (3.85%) Roma patients. The identified common haplotype in Roma patients was defined by 18 SNP markers (3.89 Mb). Fourteen common SNPs were also shared among Pakistani and Roma homozygotes. Biallelic mutation carriers suffered from prelingual bilateral moderate to profound sensorineural hearing loss.

We demonstrate different frequencies of the c.1331+2T>C mutation in hearing impaired Romanies from 3 Central European countries. In addition, our results provide support for the hypothesis of a possible common ancestor of the Slovak, Hungarian and Czech Roma as well as Pakistani deaf patients. Testing for the c.1331+2T>C mutation may be recommended in GJB2 negative Roma cases with early-onset sensorineural hearing loss.

• Age of Onset
• Alleles
• Connexin 26
• Connexins
• Czech Republic/ethnology
• Exons/genetics
• Founder Effect
• Gene Frequency
• Genotype
• Haplotypes/genetics
• Hearing Loss/congenital
• Hearing Loss/ethnology
• Hearing Loss/genetics
• Humans
• Hungary/ethnology
• Infant
• MARVEL Domain Containing 2 Protein/genetics
• Mutation
• Pakistan/ethnology
• Polymorphism, Single Nucleotide
• Prevalence
• Roma/genetics
• Sequence Homology, Nucleic Acid
• Slovakia/ethnology

• R01 DC012564 NIDCD NIH HHS
• DC011803 NIDCD NIH HHS
• R01 DC011803 NIDCD NIH HHS
• R01 DC011748 NIDCD NIH HHS
• R56 DC011803 NIDCD NIH HHS

• Ataxia
• Blindness
• CLN7
• Compound heterozygous
• IRDA
• MFSD8
• Rett like onset

Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6^nclf) mouse line to validate its utility for translational research. We demonstrate that this Cln6^nclf mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6^nclf mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

Copper, iron, and zinc are just three of the main biometals critical for correct functioning of the central nervous system (CNS). They have diverse roles in many functional processes including but not limited to enzyme catalysis, protein stabilization, and energy production. The range of metal concentrations within the body is tightly regulated and when the balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly controlled by various metal transporters and metal sequestering proteins. The biological roles of biometals are vastly reviewed in the literature with a large focus on the connection to neurological conditions associated with ageing. Biometals are also implicated in a variety of debilitating inherited childhood disorders, some of which arise soon following birth or as the child progresses into early adulthood. This review acts to highlight what we know about biometals in childhood neurological disorders such as Wilson's disease (WD), Menkes disease (MD), neuronal ceroid lipofuscinoses (NCLs), and neurodegeneration with brain iron accumulation (NBIA). Also discussed are some of the animal models available to determine the pathological mechanisms in these childhood disorders, which we hope will aid in our understanding of the role of biometals in disease and in attaining possible therapeutics in the future.

• childhood
• copper
• iron
• metals
• neurodegeneration
• zinc

• Adolescent
• Aminopeptidases
• Child
• Child, Preschool
• DNA Mutational Analysis
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• Endopeptidases/genetics
• Family
• Female
• Genetic Heterogeneity
• Genotype
• Humans
• Lysosomal Membrane Proteins
• Male
• Membrane Proteins/genetics
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Neuronal Ceroid-Lipofuscinoses/epidemiology
• Neuronal Ceroid-Lipofuscinoses/genetics
• Newfoundland and Labrador/epidemiology
• Phenotype
• Serine Proteases
• Tripeptidyl-Peptidase 1

• Animals
• Brain/metabolism
• Drosophila
• Humans
• Membrane Glycoproteins/analysis
• Membrane Glycoproteins/genetics
• Membrane Glycoproteins/metabolism
• Membrane Microdomains/metabolism
• Molecular Chaperones/analysis
• Molecular Chaperones/genetics
• Molecular Chaperones/metabolism
• Neuronal Ceroid-Lipofuscinoses/etiology
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/metabolism
• Schizosaccharomyces
• Sequence Homology, Amino Acid

• Animals
• DNA Mutational Analysis/methods
• Disease Models, Animal
• Exons/genetics
• Genetic Linkage
• Islets of Langerhans/pathology
• Islets of Langerhans/ultrastructure
• Leukocytes/pathology
• Membrane Proteins/genetics
• Microscopy, Electron, Transmission
• Molecular Sequence Data
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/metabolism
• Neuronal Ceroid-Lipofuscinoses/pathology
• Neuronal Ceroid-Lipofuscinoses/physiopathology
• Point Mutation
• Sheep Diseases
• Sheep, Domestic

• R21 NS040297-01S1 NINDS NIH HHS
• R21 NS040297-03S1 NINDS NIH HHS
• R21 NS040297-02 NINDS NIH HHS
• R21 NS040297-01 NINDS NIH HHS
• NS 40297 NINDS NIH HHS
• R21 NS040297-03 NINDS NIH HHS

• Animals
• Animals, Genetically Modified
• Animals, Newborn
• Cathepsins/genetics
• Disease Models, Animal
• Disease Progression
• Humans
• Lysosomal Membrane Proteins
• Membrane Glycoproteins/genetics
• Membrane Proteins/genetics
• Mice
• Molecular Chaperones/genetics
• Neuroglia/pathology
• Neuronal Ceroid-Lipofuscinoses/classification
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/immunology
• Neuronal Ceroid-Lipofuscinoses/pathology
• Neurons/pathology
• Thiolester Hydrolases/genetics
• Tripeptidyl-Peptidase 1
• Zebrafish/genetics

• NS41930 NINDS NIH HHS

• Age Factors
• Child
• Child, Preschool
• Humans
• Immunohistochemistry
• Infant
• Neuronal Ceroid-Lipofuscinoses/classification
• Neuronal Ceroid-Lipofuscinoses/diagnosis
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/pathology
• Vision Disorders/diagnosis

• Amino Acid Sequence
• Animals
• Genetic Linkage
• Genetic Predisposition to Disease
• Membrane Proteins/genetics
• Molecular Sequence Data
• Mutation, Missense
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/veterinary
• RNA, Messenger/metabolism
• Sequence Homology, Amino Acid
• Sheep
• Sheep Diseases/genetics
• Tripeptidyl-Peptidase 1

• NS40297 NINDS NIH HHS

• Humans
• Neuronal Ceroid-Lipofuscinoses/genetics

• Cells, Cultured
• Cholesterol/metabolism
• Chondroitin Sulfate Proteoglycans/genetics
• DNA Primers
• Fibroblasts/physiology
• Gene Expression Profiling
• Humans
• Lectins, C-Type/genetics
• Membrane Proteins/genetics
• Neuronal Ceroid-Lipofuscinoses/genetics
• Neuronal Ceroid-Lipofuscinoses/metabolism
• Oligonucleotide Array Sequence Analysis
• Reverse Transcriptase Polymerase Chain Reaction
• Skin Physiological Phenomena
• Versicans